The present invention relates to a method and composition of an oral preparation of itraconazole, an excellent azole antifungal drug. More particularly, it relates to a method and composition of an oral preparation of itraconazole having improved bioavailability, which is prepared by following steps of: i) dissolving itraconazole and hydrophilic polymer with solvent, ii) spray-drying said mixture, and iii) preparing the solid dispersions for oral preparation.
In other words, the present invention relates to an oral preparation of itraconazole, which has improved bioavailability by enhancing water solubility and rapidly being dissoluble regardless of food intake, prepared using a solid dispersions having itraconazole and pH-dependent, pharmaceutically safe, fastly dissolved at a low pH and hydrophilic polymer with the steps of i) dissolving and ii) spray-drying for the formation of an oral preparation of itraconazole having water-insoluble property.
Itraconazole or (xc2x1)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yll]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal compound, and has been considered as an efficacious and safe drug.
Itraconazole has been developed as a broad antifungal agent for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179, but usually has been administered in oral route. Further, itraconazole is efficacious in oral administration, because it has a tendency of extensive tissue distribution [Mycoses 32 (Suppl. 1), p67xcx9c87, 19891].
It has been reported that itraconazole has a pH-dependent solubility characterized in the ionization only at a low pH, such as, a gastric juice, and many attempts have been carried out to increase solubility and bioavailability, because itraconazole is almost insoluble in water (less than 1,xcexcg/ml) and in diluted acidic solution(less than 5,xcexcg/ml).
Generally, it has been reported that water insoluble drug has low dissolution property from the solid preparation. For increasing the solubility and dissolution rate of poorly water-soluble drugs, extensive studies of solubilization have shown that a wide variety of type of drugs can be efficiently solubilized by surfactants, hydrophilic carriers or pro-drugs, etc. Among them, a solid dispersion of drug and inert hydrophilic polymer has been suggested to enhance the solubility of insoluble drug. Further, many researches have been reported to enhance the solubility, dissolution rate and bioavailability of insoluble drug by preparing a solid dispersion of insoluble drug and inert carrier [{circle around (1)}International Journal of Pharmaceutics, Vol. 104, p169xcx9c174(1994), {circle around (2)}International Journal of Pharmaceutics, Vol. 143, p247xcx9c253(1996)].
The term xe2x80x9ca solid dispersionxe2x80x9d defines a system in a solid state comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. Many factors have been known to affect the solubility of a solid dispersion.
Prior references related to oral preparation for increasing bioavailability of itraconazole are as follows:
1) The solubility and bioavailability of a drug are increased by complex using cyclodextrin or its derivative in WO 85/02767 and U.S. Pat. No. 4,764,604,
2) The aerosol preparation is prepared by reducing the particle size of a drug in WO 90/11754,
3) The liposomal preparation for external use including itraconazole is prepared containing phospholipid and by solvent system in WO 93/15719,
4) The preparation for external use adhering to the nasal mucous membrane or the vaginal mucous membrane is prepared by emulsion or aqueous solution using cyclodextrin or its derivative in WO 95/31178,
5) The oral preparation to increase solubility and bioavailability of drug is disclosed in WO 94/05263, in which hydrophilic polymer such as hydroxypropyl methylcellulose is coated with about 25-30 mesh sugar spheres, and such preparation of itraconazole is commercially marketed as the trademark xe2x80x9cSPORANOXxe2x80x9d,
6) The solid dispersions comprising drug and hydrophilic polymer according to the melt-extrusion method is disclosed in WO 97/44014, in which bioavailability is improved by increasing dissolution rate of drug and food effect is minimized according to the food intake.
Generally, there is a solvent method, a melting method or a solvent-melting method, etc. for preparing solid dispersions using hydrophilic polymer as carrier. In the solvent methods, a freezing drying method, a drying method or a nitrogen-gas drying method has not a few drawbacks, low reproducibility of preparation, the higher cost of preparation and long time in the preparation, etc. In the melting method, the careful attention of working process is demanded because raising temperature over melting point affects the stability of drug and cooling condition of melting mixture also affects the property of preparation. Further, even though a solvent-melting method is carried out when a solvent method or a melting method cannot be used alone, it has not a few drawbacks, for example, a lot of manipulation steps and time.
However, the spray-drying method used in this invention has some advantages, for example, short preparation time and maintaining low temperature, because the drug and the carrier dissolved in a solvent are immediately dried after spraying. Therefore, because the stability of drug is not affected by raising temperature, the spray-drying method is efficient in industrialization.
A disclosed preparation of WO 94/05263 is concerned with the beads comprising a 25xcx9c30 mesh core, a coating film of a hydrophilic polymer and an antifungal agent, and a seal coating layer, and materials suitable for use in a fluidized bed granulator(Glatt(trademark)) with a Wurster bottom spray insert. A seal coating polymer layer is applied to the drug coated cores to prevent sticking of the beads which would have the undesirable effect of a concomitant decrease of the dissolution rate and of the bioavailability.
However, the reason why sugar sphere having appropriate dimensions(about 25-30 mesh) has to be used is to minimize the tendency toward agglomeration among sugar spheres in the drug coating process. In addition, during the preservation of the prepared beads filled in hard-gelatin capsules, sticking of the beads results in the undesirable decrease of the bioavailability. Therefore, a seal coating polymer layer has to be applied to the drug coated cores to prevent sticking of the beads. This is undesirable for demanding unnecessary step in the preparation.
On the other hand, the spraying rate in the preparation manufactured by said patent is regulated carefully to prevent undesirable drying or moisturization. Further, spraying air pressure is controlled to prevent formation of big bead and increasing of agglomeration during the coating process. Also, there is some drawbacks of spending the long time in drying, because fluidizing air volume has to be monitered carefully and inlet-air temperature has to be controlled.
The influence of food and dose on the oral bioavailability of itraconazole was studied. The relative systematic availability of itraconazole (PEG capsules) compared with solution averaged 40% in the fasting state but 102%(1.92 xcexcg h/ml) in the post-prandial state. Food did not significantly affect the rate of absorption of the capsules. Areas under the curve at single doses of 50, 100 and 200 mg had a ratio of 0.3:1:3, suggesting non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. It was also concluded from the study that to ensure optimal oral absorption, itraconazole may be administered either in capsules shortly after a meal or in solution, the absorption of which is not influenced by the presence of food in the stomach [Mycoses 32 (Suppl. 1), p67xcx9c87, 1989].
Meanwhile, the solid dispersions using the melt-extrusion method in WO 97/44014 is prepared by following steps: i) mixing the itraconazole and pharmaceutically acceptable hydrophilic polymer, ii) optionally blending additives with the thus obtained mixture, iii) heating the thus obtained blend until one obtains a homogenous melt, iv) forcing the thus obtained melt through one or more nozzles, v) cooling the till it solidifides. Obtained solid dispersions is characterized in increasing dissolution rate of drug and lowering food effect, that is, bioavailability change of drug dependent upon the food intake.
The melting temperature and melting time of polymer and drug are important factors in the solid dispersions preparation by the melt-extrusion method disclosed prior reference. In this reference, it was reported that dissolution rate of solid dispersions is decreased at a low temperature, because drug and polymer are not melted sufficiently, and that polymer cannot be used at a higher temperature owing to decomposition of polymer. Therefore, setting of melting temperature is very important. Further, to perform the cited method, extra equipment for preparing melt-extrusion and special technique to handle this equipment have to be required.
Particularly, hydrophilic polymers, such as, cellulose derivatives such as hydroxypropyl methylcellulose; natural gum such as tragacanth gum; polyvinylacetal diethylaminoacetate (trademark xe2x80x9cAEAxe2x80x9d); and polymethacrylic acid and its copolymer become char phase due to the decomposition of polymers on condition that melting time is long at relatively low temperature. The charred solid dispersions results in a serious problem of dissolution rate and stability of preparation due to the change of original character of polymer.
Also, the solid dispersions disclosed in prior reference is prepared by melt-extrusion and grinding to particles having the particle size less than 600 xcexcm in the Fitzmill twice. Then, yield of preparation is relatively low as 78%. Further, there are some drawbacks of long preparation step by adding the grinding process.
The present invention has developed the oral preparation of itraconazole having improved bioavailability prepared by preparing the solid dispersions. In this invention, the problems of prior method is solved by increasing pharmaceutical stability of heating, shortening of the manufacturing time and enhancing the yield of preparation using the spray-drying method in the solvent methods. Then, organic solvent is no longer remained in this method.
Also, the present invention developed the solid dispersions having itraconazole and pH-dependent, pharmaceutically safe, fastly dissolved at a low pH and hydrophilic polymer with the steps of i) dissolving and ii) spray-drying for the formation of an oral preparation of itraconazole having water-insoluble property. Further, the bioavailability of drug is improved and the food effect, that is, bioavailability change of drug dependent upon the food intake is minimized by increasing dissolution rate considerably in itraconazole preparation.
The object of the present invention is to provide an oral preparation of itraconazole having improved bioavailability, which is prepared by following steps of: i) dissolving 1 wt parts of itraconazole and 0.5xcx9c5.0 wt parts of pH-dependent inert hydrophilic polymer with at least one solvent selected from the group consisting of methylenechloride, chloroform, ethanol and methanol, ii) dispersing and spray-drying said mixture, and iii) preparing the solid dispersions for oral preparation.
Also, said pH-dependent inert hydrophilic polymer is at least one polymer selected from the group consisting of polyvinylacetal diethylaminoacetate and aminoalkyl methacrylate copolymer. And, said oral preparation of itraconazole is prepared by following compositions comprising 1.0xcx9c2.5 wt parts of said polymer as to 1 wt parts of itraconazole. Further, the concentration of solution dissolving itraconazole and pH-dependent inert hydrophilic polymer is 3xcx9c10% (w/w), and inlet temperature is 30xcx9c60xc2x0 C. at spray-drying.
Itraconazole has a weak basic property with pKa 3.7 and is ionized in acidic environment such as in the stomach. It has lipophilic property in nature, with oil/water partition coefficient being 5.66 in the pH 8.1 aqueous buffer/n-octanol system.
AEA(trademark) and Eudragit(trademark) E are hydrophilic polymers possessing the characteristic tertiary amine functional groups and are frequently used in protective or gastric soluble coating. Unlike other hydrophilic polymers, for example, Hydroxypropyl methylcellulose 2910, Methylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Sodium carboxymethylcellulose, etc. which release drug upon swelling, AEA(trademark) and Eudragit(trademark) E are solubilized under pH 5 in a pH-dependent manner, for increasing the dissolution profile of poorly water soluble drugs. The absorption of dissolved itraconazole from the stomach is not a problem in itself.
The pH-dependent hydrophilic polymer used in this invention, for example, polyvinylacetal diethylaminoacetate (trademark xe2x80x9cAEAxe2x80x9d) or aminoalkyl methacrylate copolymer (trademark xe2x80x9cEudragit Exe2x80x9d) is dissolved in acid solution only at a pH in the range of 1xcx9c5. Further, 0.5xcx9c5.0 wt parts of said pH-dependent hydrophilic polymer, preferably, in the range of 1.0xcx9c2.5 wt parts of the polymer is contained as to 1 wt parts of insoluble drug. In case that the content of polymer is less than 0.5 wt parts, the solubility of drug with carrier shall decrease, because a solid dispersions is not formed completely, and such fact is confirmed by observing endothermic peak by melting of drug in Differential Scanning Calorimetry. In case that the content of polymer is more than 5.0 wt parts, initial dissolution rate shall decrease by polymer, and patient adaptability can be reduced by big size of preparation in taking drug.
The oral preparation in this invention is prepared by preparing the solid dispersions, which can be mass-produced in a large amount using spray dryer. The organic solvent, such as, methylenechloride or chloroform is used for dissolving insoluble drug and hydrophilic polymer before spray-drying, and methanol or ethanol can be mixed to said solution. The amount of solvent for spray-drying shall be required in the concentration of hydrophilic polymer to be 3xcx9c10% (w/w), preferably, 5% (w/w). Also, inlet temperature of dissolved mixture is 30xcx9c60xc2x0 C., preferably, 35xcx9c45xc2x0 C., and inlet amount of dissolved mixture can be changed properly according to the concentration of polymer. The yield of solid dispersions may be more than 95%.
Also, the solid dispersions used in this invention can be manufactured as not only tablet but form of oral preparation, such as, powder, granule, granule capsule, pellet capsule by the known method. Therefore, there are many choices in preparation development.
The diluent can be added to solid dispersions in order to manufacture oral preparation in this invention. For example, lactose, starch, sodium starch glycolate (Explotab(trademark)), crospovidone (Kollidone CL(trademark), Kollidone CL-M(trademark)), croscarmellose sodium (AC-Di-Sol(trademark)) or maltodextrin (Maltrine(trademark)) is used as a disintegrant in preparation. Further, stearic acid, magnesium stearate or talc is used as a lubricant.